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Article Cite This: Mol. Pharmaceutics XXXX, XXX, XXX−XXX

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Linking the Gastrointestinal Behavior of Ibuprofen with the Systemic Exposure between and within HumansPart 2: Fed State

Mol. Pharmaceutics Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 11/15/18. For personal use only.

Paulo Paixão,†,‡,£ Marival Bermejo,†,§,£ Bart Hens,†,∥,£ Yasuhiro Tsume,†,£ Joseph Dickens,⊥,£ Kerby Shedden,⊥,£ Niloufar Salehi,#,£ Mark J. Koenigsknecht,† Jason R. Baker,∇,£,△ William L. Hasler,∇,£,△ Robert Lionberger,○,£ Jianghong Fan,○,£ Jeffrey Wysocki,† Bo Wen,† Allen Lee,∇,△ Ann Frances,† Gregory E. Amidon,† Alex Yu,† Gail Benninghoff,† Raimar Löbenberg,◆ Arjang Talattof,† Duxin Sun,† and Gordon L. Amidon*,†,£ †

Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, Michigan 48109−1065, United States ‡ Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Avenida Professor Gama Pinto, 1649-003 Lisboa, Portugal § Department of Engineering, Pharmacy Section, Miguel Hernandez University, San Juan de Alicante, 03550 Alicante, Spain ∥ Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49, 3000 Leuven, Belgium ⊥ Department of Statistics and ∇Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan 48109, United States # Center for the Study of Complex Systems and Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109-2136, United States ○ Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland 20993, United States ◆ Faculty of Pharmacy & Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2H7 △ Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan 48109, United States S Supporting Information *

ABSTRACT: Exploring the intraluminal behavior of an oral drug product in the human gastrointestinal (GI) tract remains challenging. Many in vivo techniques are available to investigate the impact of GI physiology on oral drug behavior in fasting state conditions. However, little is known about the intraluminal behavior of a drug in postprandial conditions. In a previous report, we described the mean solution and total concentrations of ibuprofen after oral administration of an immediate-release (IR) tablet in fed state conditions. In parallel, blood samples were taken to assess systemic concentrations. The purpose of this work was to statistically evaluate the impact of GI physiology (e.g., pH, contractile events) within and between individuals (intra and intersubject variability) for a total of 17 healthy subjects. In addition, a pharmacokinetic (PK) analysis was performed by noncompartmental analysis, and PK parameters were correlated with underlying physiological factors (pH, time to phase III contractions postdose) and study parameters (e.g., ingested amount of calories, coadministered water). Moreover, individual plasma profiles were deconvoluted to assess the fraction absorbed as a function of time, demonstrating the link between intraluminal and systemic behavior of the drug. The results demonstrated that the in vivo dissolution of ibuprofen depends on the present gastric pH and motility events at the time of administration. Both intraluminal factors were responsible for explaining 63% of plasma Cmax variability among all individuals. For the first time, an in-depth analysis was performed on a large data set derived from an aspiration/motility study, quantifying the impact of physiology on systemic behavior of an orally administered drug product in fed state conditions. The data obtained from this study will help us continued...

Received: July 12, 2018 Revised: September 11, 2018 Accepted: October 15, 2018

© XXXX American Chemical Society

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DOI: 10.1021/acs.molpharmaceut.8b00736 Mol. Pharmaceutics XXXX, XXX, XXX−XXX

Article

Molecular Pharmaceutics

to develop an in vitro biorelevant dissolution approach and optimize in silico tools in order to predict the in vivo performance of orally administered drug products, especially in fed state conditions. KEYWORDS: in vivo study, in vivo dissolution, local drug concentration in the GI tract, ibuprofen, immediate release, bioequivalence, bioavailability, oral absorption, buffer capacity, motility, manometry, fed state

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INTRODUCTION Recommendations regarding the intake of drug product are approved and described by the summary of product characteristics (SmPC) after testing the product in humans under strict and predefined conditions. The prescribed guidelines may differ slightly between different agencies around the world. For instance, the U.S. Food and Drug Administration (FDA) promulgates coadministration of 240 mL (8 fluid ounces) of water to test the performance of the oral drug product under fasted state test conditions.1,2 The European Medicines Agency (EMA) indicates that a standardized volume of “at least 150 mL of fluid” should be considered to test oral drug products in fasted state conditions.3 Further, the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan recommends administration of 100−200 mL (normally 150 mL) of water together with the oral drug product in clinical studies.4 In the case of testing the oral drug product under fed state conditions, the FDA and EMA apply the same protocol, which indicates that subjects should consume a high-fat (approximately 50% of total caloric content of the meal) and high-calorie (approximately 800 to 1000 kcal) meal in 30 min, prior to administration of the drug product. The composition of the meal should clearly be described in the percentage of calories for the present proteins, carbohydrates, and fat content (150, 250, and 500− 600 kcal, respectively). The test meal that is prescribed by FDA guidelines is the standardized FDA breakfast meal including two eggs fried in butter, two strips of bacon, two slices of toast with butter, four ounces of hash brown potatoes, and eight ounces of whole milk. However, substitutions in this test meal are allowed as long as the meal provides a similar amount of calories from protein, carbohydrate, and fat and has comparable meal volume and viscosity. In contrast, the PDMA recommends a low-fat diet of 700 kcal or less containing not more than 20% by the energy of the lipid with no further specifications regarding the volume or amount of calories for the present nutrients (i.e., proteins, carbohydrates, and fat) in the administered test meal. In vitro solubility studies have already shown the effect of the type of meal (fed versus fat-enriched fed state) on the solubility of nonionized drugs. Clarysse et al. demonstrated that the solubility of nonionized compounds in time-dependent aspirated human intestinal fluids (HIF) was higher in early intestinal fractions whenever a fat-enriched meal (300 mL of Scandishake Mix; 46% fat content) was administered compared to a “normal” fed meal (400 mL of Ensure Plus; 29% fat content).5 Authors concluded that this measured difference in solubility would be a source of variability in intestinal drug absorption and thus systemic availability. The administered volumes of meals, and thus, the fat content, may create different scenarios of the present (mixed) micelles and lipid vesicles in the intestinal tract in such a way that the available solubilized fraction of drug may significantly be altered.6 Nevertheless, the administered amount of calories will also impact and affect the GI physiology as, for instance, gastric emptying. Regulation of gastric emptying of caloric meals depends on numerous factors such as meal structure (solid

versus liquid) and composition (caloric content of present proteins, carbohydrates, and fat). In the case of solid meals, Camilleri et al. demonstrated a biphasic process of gastric emptying, consisting of a lag phase followed by a gastric emptying phase.7 The lag phase is considered as the time the stomach needs to process the ingested solids.8,9 In the case of liquid meals, this lag phase prior to gastric emptying is absent, whereas the rate of gastric emptying depends on the caloric density of the liquid meal.10−12 For instance, the higher the fat content of the meal, the more gastric emptying will be delayed, presumably by a difference in meal distribution along the stomach and/or differences in intragastric hydrodynamics.13−15 The emptying of noncaloric liquids (e.g., water) is initially rapid and subsequently slow, typically following a first-order kinetic pathway.16,17 On the basis of these data, it could be stated that the administered volume of the meal/amount of calories during bioequivalence (BE) studies may alter systemic exposure of the tested oral drug product, resulting in potential failures. Although each regulatory authority strictly defines the meal composition that should be ingested, one could be concerned about the different meal compositions as prescribed by each regulatory authority. Moreover, a discussion could be held that raises the question if the prescribed meal is relevant for the “real-life” dosing situation: will patients ingest the same meal with respect to size and calories as applied in the BE studies? This is a topic that requires an extensive debate and could, hopefully, lead to a globally harmonized guideline to address this issue. The aim of this study was to map how the underlying GI physiology is responsible for differences in systemic outcome (in terms of plasma Tmax, Cmax, and AUC) of a drug product after oral administration under fed state conditions. Most of the aspiration studies are performed under fasting state conditions, but physiology will change tremendously whenever an oral drug product is administered in fed state conditions (e.g., gastric emptying). To explore these events, an aspiration/motility study was performed at the University Hospital of Michigan. In a previous study, the intraluminal behavior and systemic exposure of an orally administered immediate-release tablet of ibuprofen (800 mg; reference listed drug) were investigated in healthy subjects.18,19 After oral administration, GI fluids were aspirated and analyzed for drug content. In parallel, blood samples were collected. Pressure events along the GI tract were measured to evaluate the impact of GI motility on drug product performance. In this work, we will perform an in-depth statistical and pharmacokinetic analysis to assess correlations between underlying physiological variables and the systemic exposure of the drug. In that way, the impact of physiology on the systemic exposure of a drug can be quantified. Moreover, the influence of the ingested amount of calories will be statistically investigated, as the healthy subjects were not obliged to ingest the total amount of meal in this study. The results of this study generate a scientific framework that will help formulation scientists to adequately evaluate the performance of oral drug products in fed state conditions by applying an optimized in vitro predictive dissolution methodology in an early phase of drug product development. B


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MATERIALS AND METHODS Chemicals. Ibuprofen tablets (800 mg, reference listed drug product) were obtained from Dr. Reddy’s Laboratories Inc. (Shreveport, LA; IBUIbuprofen Tablets, USP, 800 mg, Lot no. 400603) through the University of Michigan Hospital. Phenol red was obtained from U.S. Pharmacopeia (Rockville, MD). Trifluoroacetic acid (TFA), formic acid, methanol, and acetonitrile were obtained from Fisher Scientific Inc. (Pittsburgh, PA). All chemicals were of analytical grade or HPLC grade. In Vivo Study Design. The study was performed at the University of Michigan Hospital after receiving approval by the internal review board (IRB) at both the University of Michigan and FDA (HUM00085066) under project number HHSF223201310144C. The study was registered at clinicaltrials.gov (NCT number (NCT02806869). Koenigsknecht et al. recently described the design of the study in detail.19 Briefly, 12 volunteers (7 men and 5 women) were recruited to explore the GI behavior of ibuprofen after oral administration of the IR tablet of ibuprofen in fed state conditions; 5 out of 12 subjects participated in the study twice to generate intrasubject variability data. All volunteers provided written informed consent to participate in this study. After a fasting period, a customized multilumen GI tube from MUI Scientific (Mississauga, Ontario) was introduced via the mouth to the small intestine. Abdominal fluoroscopy was performed to ensure the GI tube was properly positioned in the different regions of the GI tract (i.e., stomach, duodenum, proximal, and distal jejunum). The subject was asked to remain in bed while the GI tube was equilibrated by performing a baseline GI motility test for approximately 3−5 h (Medical Measurement Systems (MMS), Williston, Vermont). Prior to administration of the ibuprofen tablet, an intravenous catheter was introduced in the antecubital area of the subject for blood collection. The catheter was kept open with heparin and saline solution. The subjects were asked to empty his/her urine bladder prior to the start of the study. At approximately 4:00 AM, and to induce fed state conditions, volunteers were asked to drink a liquid meal (two cans of Pulmocare). Two cans of Pulmocare have a total volume of 474 mL, containing 29.6 g of proteins, 44.2 g of fat, 25 g of carbohydrates, and a total amount of 710 calories. Volunteers were not obliged to drink the total volume in order to prevent nausea prior to the start of the study. After the ingestion of the liquid meal (within a 10 min period), the subject was also given a single oral dose of ibuprofen (800 mg tablet). The study drug was administered with 250 mL of water containing USP grade phenol red (0.1 mg/mL). The actual amount of water consumed was measured and recorded. Again, volunteers were not obliged to drink the total amount of administered water to avoid any feeling of nausea at the start of the study. GI samples (i.e., stomach, duodenum, and jejunum) were collected at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, and 7 h. Plasma samples (4 mL/time point) were collected at 0, 0.167, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 12, and 28 h. The pH values of GI fluid samples were immediately measured and recorded. The GI fluid samples were centrifuged at a speed of 17 000g for 10 min, and the supernatant was placed in the new tube for drug concentration analysis. All samples were stored in the −80 °C freezer until analysis of ibuprofen and phenol red. Analysis of Ibuprofen in the Aspirated GI Fluids and Plasma Samples. A validated LC−MS/MS analysis method in a biorelevant matrix was applied to accurately and precisely measure the ibuprofen solution and total concentrations in the GI fluids and plasma samples. With respect to the handling and

analysis of the samples, the authors would like to refer the reader to a recently published manuscript by Hens and colleagues.18 The analysis methods passed the FDA requirements with accuracy and precision errors less than 15%. Intraluminal Recording of Pressure Events along the Human GI Tract. MMC phase III motility periods were identified from the water-perfused manometric measurements using spectral density estimation and penalized logistic regression as described in detail by Hens and colleagues.18 Briefly, motility pressure events were analyzed and classified as follows: powerful antral phase III contractions were defined as the regular occurrence of at least 2 contractions per minute for a period of no less than 2 min with an average amplitude of 75 mmHg. Duodenal phase III contractions are characterized by a rate of at least 11 contractions per minute with an average amplitude of 33 mmHg lasting at least 3 min. The time of appearance of phase III postdose activity was an important physiological variable responsible for emptying a large quantity of drug product from stomach into small intestine. A representative illustration of a postdose phase III contraction (tMMC-III) is depicted in Figure 1. pH Determination of the Aspirated GI Fluids. Immediately after aspiration of the GI fluids, pH was measured ex vivo using a pH electrode (Mettler InLab Micro Pro, MettlerToledo LLC, Columbus, OH), suitable for measuring pH in small or large volumes. Pharmacokinetic Evaluation and Deconvolution of Plasma Profiles. Pharmacokinetic (PK) evaluation of the plasma profile after oral administration in each subject was made by means of noncompartmental analysis (NCA) with the program PK-Solver,20 an add-in software for PK and pharmacodynamic (PD) data analysis in Microsoft Excel (Redmond, WA), using the NCA Extravascular module and the linear trapezoidal method. Statistical correlations between the PK, physiology (e.g., luminal pH and time to phase III contractions postdose), and/or other parameters (e.g., amount of ingested calories, liquid volumes) were made using linear models and the software Statgraphics Centurion XV (The Plains, VA). The fraction absorbed of ibuprofen as a function of time and ibuprofen absorption rates after oral administration were estimated in each subject from their plasma levels by numerical deconvolution using the software PK-Quest21 and the ibuprofen intravenous (IV) data from Chassard et al.22 to model the systemic bolus input function. Duodenum (CD) and jejunum (CJ) luminal concentrations were related to the ibuprofen rate of absorption by fitting the “rate-in-a-tube” as reflected in eq 1 absorption rate = (2 × π × r × LD × Peff × CD) + (2 × π × r × LJ × Peff × CJ)

(1)

assuming an intestinal radius of 1.75 cm, an ibuprofen effective permeability (Peff) of 1.91 × 10−4 cm/h,23 and adjusting the absorption zone length at the duodenum (LD) and jejunum (LJ) by nonlinear regression.

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RESULTS The individual and average plasma profiles are presented in Figure 2, and luminal stomach, duodenum, and jejunum concentrations are presented in Figure 3A−C. Main noncompartmental PK parameters and other clinical and physiological data are summarized in Table 1. All reported elimination half-lives were calculated based on the elimination rate constant determined by using, at least, three data points in the elimination log-phase. Between-subject and within-subject variability, based C


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Figure 1. Illustration of the initiation of phase III contraction in subject 20 (visit 1) who ingested 420 calories of the Pulmocare meal. Motility pressure events were recorded via water-perfused manometry. Ports 1−3 represent the stomach; ports 4−6 represent the duodenum; ports 7−9 represent the jejunum.

Table 2 provides the absorbed amount of ibuprofen at different time values when 25, 50, and 75% of the ibuprofen absorption was completed. Calculations were based on plasma numerical deconvolution. Individual luminal profiles of the duodenum and jejunum were compared with the individual deconvolution absorption rates (Supplementary Figure S1), and in general, good matches were observed. As such, a mass transfer analysis (MTA) based on the “rate-in-a-tube” model was performed in order to relate these individual luminal concentrations to the in vivo absorption rate. After fitting the effective length of the duodenum and jejunum with values of 22 and 36 cm (indicating the position of the suction channels on the catheter to aspirate jejunal fluids), respectively, the following predicted versus observed absorption rates were obtained (Figure 4A) as well as the average observed and predicted absorption rate as a function of time (Figure 4B). Figure 5A−C presents the median luminal pH as well as the luminal ibuprofen concentrations in the stomach (A), duodenum (B), and jejunum (C). In addition, the pKa value of ibuprofen

Figure 2. Individual (gray) and mean (green) plasma profiles as a function of time for all subjects after oral administration of 800 mg ibuprofen IR tablets in fed state conditions.

on ANOVA with log-transformed values, was approximately 30% for the Cmax and 11 and 34% for AUC, respectively.

Figure 3. Individual and mean luminal solution concentrations as a function of time of ibuprofen after the oral administration of an 800 mg ibuprofen IR tablet in fed state conditions (from the left to the right: stomach, duodenum, and jejunum). D


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Table 1. Pharmacokinetic, Clinical, and Physiological Parameters after the Administration of an 800 mg Ibuprofen Tablet on Postprandial Conditionsa subject

visit

tmax (h)

Cmax (μg/mL)

AUCt (μg·h/mL)

t1/2 (h)

CAL

tMMC (h)

vol (mL)

St pH

D pH

B002 B002 B008 B020 B020 B022 B022 B026 B031 B034 B041 B043 B043 B046 B060 B060 B066

1 2 1 1 2 1 2 1 1 1 1 1 2 1 1 2 1 mean geo mean SD CV (%) median range

1.5 8.0 3.0 3.0 4.0 6.0 5.0 7.0 6.0 7.0 4.0 6.0 5.0 8.0 1.5 1.0 7.0

9.12 5.70 66.40 40.50 33.40 39.20 26.57 39.90 48.00 56.97 64.57 32.00 55.70 12.50 23.00 25.80 50.70 41.0 37.7 15.9 39

80.5 100.2 318.1 337.9 158.3 175.3 243.5 186.1 240.7 246.0 275.9 191.0 211.9 125.2 133.9 141.7 226.7 214.2 205.2 64.5 30

3.46

600 355 380 420 486 594 711 681 261 659 11 711 711 561 704 711 539 543 429 204 38

5.33 2.11 4.03 5.25 4.83 6.53 4.92 3.80 3.24 2.75 1.00 6.17 5.38 7.00 5.25 6.67 4.50 4.75 4.37 1.62 34

648 387 463 519 574 646 536 654 324 649 339 642 599 475 718 724 563 562 548 122 22

5.11 5.40 5.76 3.62

5.94 6.41 3.57 6.70

2.73 2.68 2.11 4.33 1.84 2.28 1.88 2.04 2.12 3.84 2.12 1.88 2.49 2.39 0.81 32

3.59 4.49 5.14 6.16 2.19 1.80 3.24 2.15 4.48 4.71 3.40 6.60 4.10 3.81 1.51 37

6.26 5.90

6.36 5.38 5.72 5.78 4.09 4.86 4.80 5.40 5.31 0.98 18

5.0 (1−8)

“St pH” and “D pH” stands for “stomach pH” and “duodenal pH”, respectively. The time to phase 3 contractions postdose is given by the abbreviation “tMMC”. The amount of calories that each subject ingested in given by the “CAL” column.

a

Table 2. Different Time Values of When 25, 50, and 75% of the Ibuprofen Absorption Was Completeda T25% abs

T50% abs

subject

h

h

T75% abs h

B008V1 B020V1 B020V2 B022V1 B022V2 B026V1 B031V1 B034V1 B041V1 B043V1 B043V2 B046V1 B060V1 B060V2 B066V1 mean CV% min max

1.30 2.02 2.45 3.94 3.12 4.75 2.54 5.95 2.83 3.74 4.22 4.80 0.67 0.91 5.66 3.26 51 0.67 5.95

2.57 2.95 3.05 4.63 7.01 5.78 4.15 6.67 3.31 4.66 4.90 7.01 1.20 2.21 6.53 4.44 42 1.20 7.01

3.22 4.61 3.70 5.38 13.68 6.82 5.04 7.39 3.89 5.62 6.14 9.26 4.08 3.22 7.34 5.96 46 3.22 13.68

a

Calculations were based on plasma numerical deconvolution.

(∼4.85), the average tMMC-III, and the theoretical solubility are depicted as well. The theoretical solubility was based on the intrinsic solubility of 68 μg/mL and the pH-dependent ionization of ibuprofen. The theoretical solubility at each pH is calculated based on its intrinsic solubility and the observed pH of the GI fluids. The stomach concentrations are typically low due to the observed pH (mostly below ibuprofen’s pKa value). In the duodenum and jejunum, pH values are above the pKa, and

Figure 4. (A) Predicted versus observed absorption rates and (B) the average observed and predicted absorption rates as a function of time.

saturation conditions are only observed in the duodenum at later time points. E


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Figure 5. Median luminal pH and ibuprofen concentrations in the stomach (A), duodenum (B), and jejunum (C). The pKa value of ibuprofen (∼4.85), the average tMMC-III, and the theoretical solubility are presented as well. Data were extracted from Hens et al.18

Figure 6A−D presents the correlations between some of the physiological and in vivo data of Table 1 and the individual ibuprofen Cmax values. As can be seen, strong correlations were observed between the amount of ingested calories and the

tMMC-III. No significant correlations were observed with the average pH in the stomach and duodenum, although in the first case and because of the observed shape of the correlation, a possible interaction with other variables may occur. F


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Figure 6. Linear-regression analysis between plasma Cmax (μg/mL) and (A) average stomach pH, (B) ingested amount of calories, (C) average duodenum pH, and (D) time to phase III contractions postdose.

On the basis of the above observations, a multiple-linear regression was performed, considering the results and variables available in Table 1 and also the interactions between the remaining variables: tMMC, ingested amount of calories, average stomach pH, interaction between average stomach pH and tMMC-III, average duodenal pH, ingested coadministered water, the interaction between the average stomach pH and the coadministered water, and the interaction between average stomach pH and ingested amount of calories. As a result of the low number of complete cases (n = 11), all possible models combining at most three variables were considered and ordered by relevance based on the adjusted R2. Finally, the statistical significance of each included variable in the final model was tested by ANOVA. The final best model included the stomach pH (independent variable 1) and an interaction between the stomach pH and the tMMC-III parameter (independent variable 2), with the following (eq 2)

Figure 7. Performance of the multiple-linear-regression model that was able to predict the individual plasma Cmax, considering the tMMC-III and average stomach pH as key variables.

Figure 7. This equation is only intended to explain the variability observed in ibuprofen plasma Cmax. No extrapolation is ever intended at this time for other doses.

Cmax = 54.55 + 7.89 × (average stomach pH) − 2.31 × (tMMC × average stomach pH)

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(2)

DISCUSSION Although the in vivo study tried to follow the guidelines and procedures for a general BE fed study, it is important to

This model is able to explain 63% of the observed variability in ibuprofen plasma Cmax, and its performance can be observed in G


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Figure 8. Comparison between different PK indicators from the present study and from other studies of ibuprofen in the literature performed in fed state conditions (doses normalized for an 800 mg dose).

and is, in some cases, still occurring 13 h after oral administration. This slower and prolonged absorption process resulted in a lower Cmax, delayed tmax, and slightly reduced AUC, as compared to the fasting state data.18 In order to explain this overall postprandial behavior, a correlation analysis was undertaken, between considering the more variable PK parameter, Cmax, and the in vivo and physiological variables in the studied population. The strongest correlations to Cmax were observed with the amount of ingested calories and the tMMC-III. In a recent paper, Abuhelwa et al. identified a direct linear relationship between the amount of ingested calories and the observed gastric transit time by performing a meta-analysis.30 Besides delaying gastric emptying, food is also known to change the contractile pattern of the GI motility. After intake of a meal, the interdigestive migrating motor complex (MMC) will be interrupted, and the types of contractions that will be observed during meal digestion are similar to the ones observed during a phase II of the fasting MMC.31 In this context, the duration of the fed pattern can be defined as the interval between the loss of the fasted pattern and the return of a burst of rhythmic activity propagating distally, defined as a phase III event (tMMC-III), and the time to onset of these phase III contractions after a meal has also been shown to increase with the caloric content of the meal.32 There is also a good correlation (r = 0.654) between the amount of ingested calories and the appearance of the tMMC-III in our data, indicating that both ingested calories and tMMC-III are influencing Cmax by means of slow gastric emptying. In the case of plasma Cmax, gastric emptying seems to be the major factor roughly explaining 53% of the variability in systemic exposure. As we take into account a lot of physiological variables in this study, we are still not aware of the residual fluids at the time of aspiration that may have a major impact on systemic variability. As observed for the fasted state, the measured pockets of fluid along the GI tract consist of only a few milliliters.33,34 Future work should focus on the measurement of

understand if the intubation procedure was not affecting drug absorption and/or disposition. For example, it is known that pain and discomfort can delay gastric emptying and thus affects the onset of drug absorption. That was probably the case with one subject (subject B002) that during the in vivo procedure, some discomfort was reported. This subject also presented an ibuprofen plasma profile significantly different from that of the remaining subjects, with lower plasma Cmax and AUC (Table 1), and for these reasons, was removed from the remaining analysis. Figure 8 summarizes the comparison of the plasma Cmax, AUC, and elimination t1/2 values obtained in this study with the average plasma Cmax, AUC, and elimination t1/2 values across several different in vivo trials of immediate-release ibuprofen oral products under fed conditions.24−28 All plasma Cmax and AUC values were normalized to an 800 mg dose. On the basis of this comparison, there seems not to exist any significant differences between the results from our study and the results that are out there in the literature, confirming that there is no interference of the transpyloric tube on the PK of ibuprofen.29 Regarding variability under fed conditions, between-subject variability in plasma Cmax and AUC seems to be approximately 25% as reported in two studies comparing fasted versus fed PK of IR tablets of ibuprofen.25,28 Within-subject variabilities were approximately 20 and 11% for plasma Cmax and AUC, respectively, based on the 90% confidence interval for the fed/fast ratio reported in the same studies. Taking into account that we only have within-subject data for four subjects, variability in our data seems to be similar to the variability reported in the literature. As the oral profiles obtained in this study presented reasonable similarity with other studies, IV reported data were used to perform the PK analysis and deconvolution of oral profiles under the assumption of similar disposition parameters. As can be derived from Table 2, the absorption process in postprandial conditions is prolonged over time, with 50% of the absorption process occurring around 4.4 h after administration. There is, however, a large variability observed in the absorption process H


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Molecular Pharmaceutics residual fluid volumes after intake of a meal to see how these pockets will evolve. Any of the other studied parameters seemed to be explaining the remaining variability in the Cmax parameter, although the average pH of the gastric content presented a graphical tendency that could be indicative of a possible interaction with another variable. As such, a multiple-linear regression was undertaken in order to explore the effect of multiple and possible associated variables in explaining the observed variability in Cmax. The resulting model (eq 2) clearly indicated that (1) the higher the interaction value of tMMC-III and average stomach pH, the lower the ibuprofen plasma Cmax; and (2) the higher the average stomach pH, the higher the ibuprofen plasma Cmax. The combination of these two factors is able to explain 63% of the ibuprofen plasma Cmax variability. From the above findings, it is clear that physiological gastric variability was responsible for much of the observed variability in the PK plasma behavior of ibuprofen. A good correlation was also observed between the duodenal/jejunal solution concentrations and the rate of plasma appearance of ibuprofen (Figure 4A,B) using the “rate-in-a-tube” model. In this regard, Figure 4A−C shows both the effect of motility and pH on the luminal ibuprofen solution concentrations in the stomach, duodenum, and jejunum, based on average data. Ibuprofen is an acidic (pKa ≈ 4.85), low-solubility drug (intrinsic solubility = 68 μg/mL).35 Consequently, the dissolution rate depends on luminal pH. As can be observed in Figure 6A, ibuprofen concentrations in the stomach are always reaching the level of solubility. In the stomach, the observed pH is never sufficient for a complete dissolution of the administered amount of ibuprofen. As such, ibuprofen is being released from the stomach both as dissolved drug but mainly as solid particles. This release is being performed over a time span of 4−5 h. In the duodenum and jejunum (Figure 5B,C), luminal concentrations of dissolved ibuprofen are, most of the time, below the theoretic solubility at the corresponding luminal pH. All individual pH profiles in the different segments of the GI tract are depicted in Supplementary Figure 2. In the duodenum, only at times near the tMMC-III, some saturation is observed. This indicates that at initial times, the amount of drug released from the stomach is, probably because of a slow release rate and a sufficient amount of water, easily dissolved. However, close to the tMMC-III (also known as the “house-keeper wave”), the residual content of the stomach will be emptied from the stomach into the duodenum. Finally, when reaching the jejunum, the amount of drug is fully dissolved, as the driving force for dissolution was maintained thanks to (i) the increase in solubility at higher pH values and because of (ii) the disappearance by the high membrane permeability.36 On the basis of the overall findings, it was seen that ibuprofen oral absorption in postprandial conditions depends on (i) stomach pH and (ii) the time to phase III contractions postdose. As a result of these observations, most of the ibuprofen absorption variability is related to the variability in the GI conditions, which can be responsible for potential in vivo BE failures. In this situation, and in order to deal with the (intra) subject variability, standardized conditions should be used. That is the case with the guideline requirements regarding the amount of food ingested, which typically consists of a meal containing 800 calories.2−4 The ingested amount of food has a significant effect on the gastric transit time. However, as can be seen in Table 1 for specific subjects that ingested more than 600 calories, the stomach pH varied from 2.15 to 5.14. This is something that is hard to control and will not eliminate the variability in the

stomach pH, as a low and variable buffer capacity is observed in the stomach.18 The complex environment of the stomach needs more attention and should be further investigated in future studies.

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CONCLUSION In summary, this work presents the experimental proof that in vivo dissolution of ibuprofen (BCS class 2a) depends on luminal pH and present motility events at the time of administration. The relationship between the gastric pH and the rate of gastric emptying determines the rate of arrival of ibuprofen to the small intestine. Finally, absorption rates in plasma are clearly governed by the intestinal ibuprofen solution concentrations as they determine the driving force for the diffusion/permeation process through the intestinal membrane. For the first time, this work unraveled the impact of physiological variables on the systemic of a drug for a large number of subjects and quantified that using linear regressions. The application of the “rate-in-a-tube” approach, assessing the absorption rate based on observed luminal solution concentrations of ibuprofen, matched reasonably well with the absorption rates deconvoluted from the plasma profiles. The statistical and pharmacokinetic approach can be used for more clinical aspiration/motility studies in the future to assess the impact of physiology on the systemic exposure of a drug. The obtained in vivo dissolution data and the information from the relevant physiological variables can be used to refine our current prototypes of the gastrointestinal simulator (GIS) and other predictive in vitro models as well as in silico models to adequately predict the systemic exposure of the drug.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.molpharmaceut.8b00736. Supplementary Figure S1: Individual luminal profiles of the duodenum and jejunum compared with the individual deconvolution absorption rates; Supplementary Figure S2: All individual pH profiles in the different segments of the human GI tract (PDF) R Related Articles *

The authors would like to refer the reader to Part 1 of this study, which describes the results of this study related to the fasting state conditions.

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AUTHOR INFORMATION

Corresponding Author

*Phone: +(1) 734-764-2226; Fax: +(1) 734-764-6282; E-mail: [email protected] (G.L.A.) ORCID

Bart Hens: 0000-0002-4229-9843 Alex Yu: 0000-0003-1732-2631 Arjang Talattof: 0000-0002-8783-6518 Gordon L. Amidon: 0000-0003-0355-911X Author Contributions £ P.P., M.B., B.H., Y.T., J.D., K.S., N.S., R.L., J.F., J.R.B., W.L.H., and G.L.A. are the primary authors/contributors.

Notes

The authors declare no competing financial interest. I


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(17) Hasler, W. L. In Textbook of Gastroenterology, 5th ed.; Yamada, T., Alpers, D. H., Kalloo, A. N., Kaplowitz, N., Owyang, C., Powell, D. W., Eds.; Blackwell Publishing Ltd., 2009; pp 207−230. (18) Hens, B.; Tsume, Y.; Bermejo, M.; Paixao, P.; Koenigsknecht, M. J.; Baker, J. R.; Hasler, W. L.; Lionberger, R.; Fan, J.; Dickens, J.; Shedden, K.; Wen, B.; Wysocki, J.; Loebenberg, R.; Lee, A.; Frances, A.; Amidon, G.; Yu, A.; Benninghoff, G.; Salehi, N.; Talattof, A.; Sun, D.; Amidon, G. L. Low Buffer Capacity and Alternating Motility along the Human Gastrointestinal Tract: Implications for in Vivo Dissolution and Absorption of Ionizable Drugs. Mol. Pharmaceutics 2017, 14, 4281−4294. (19) Koenigsknecht, M. J.; Baker, J. R.; Wen, B.; Frances, A.; Zhang, H.; Yu, A.; Zhao, T.; Tsume, Y.; Pai, M. P.; Bleske, B. E.; Zhang, X.; Lionberger, R.; Lee, A.; Amidon, G. L.; Hasler, W. L.; Sun, D. In Vivo Dissolution and Systemic Absorption of Immediate Release Ibuprofen in Human Gastrointestinal Tract under Fed and Fasted Conditions. Mol. Pharmaceutics 2017, 14, 4295−4304. (20) Zhang, Y.; Huo, M.; Zhou, J.; Xie, S. PKSolver: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput. Methods Programs Biomed 2010, 99, 306− 314. (21) Levitt, D. G. PKQuest_Java: free, interactive physiologically based pharmacokinetic software package and tutorial. BMC Res. Notes 2009, 2, 158. (22) Chassard, D.; Geneteau, A.; Gualano, V.; Brault, M. Bioequivalence study of two Ibuprofen formulations administered intravenously in healthy male volunteers. Clin. Drug Invest. 2004, 24, 739−747. (23) Paixão, P.; Gouveia, L. F.; Morais, J. A. G. Prediction of the human oral bioavailability by using in vitro and in silico drug related parameters in a physiologically based absorption model. Int. J. Pharm. 2012, 429, 84−98. (24) Davies, N. M. Clinical pharmacokinetics of ibuprofen. The first 30 years. Clin. Pharmacokinet. 1998, 34, 101−154. (25) Kapil, R.; Nolting, A.; Roy, P.; Fiske, W.; Benedek, I.; Abramowitz, W. Pharmacokinetic properties of combination oxycodone plus racemic ibuprofen: two randomized, open-label, crossover studies in healthy adult volunteers. Clin. Ther. 2004, 26, 2015−2025. (26) Klueglich, M.; Ring, A.; Scheuerer, S.; Trommeshauser, D.; Schuijt, C.; Liepold, B.; Berndl, G. Ibuprofen extrudate, a novel, rapidly dissolving ibuprofen formulation: relative bioavailability compared to ibuprofen lysinate and regular ibuprofen, and food effect on all formulations. J. Clin. Pharmacol. 2005, 45, 1055−1061. (27) Tanner, T.; Aspley, S.; Munn, A.; Thomas, T. The pharmacokinetic profile of a novel fixed-dose combination tablet of ibuprofen and paracetamol. BMC Clin. Pharmacol. 2010, 10, 10. (28) Levine, M. A.; Walker, S. E.; Paton, T. W. The effect of food or sucralfate on the bioavailability of S(+) and R(−) enantiomers of ibuprofen. J. Clin Pharmacol 1992, 32, 1110−1114. (29) Müller-Lissner, S. A.; Fimmel, C. J.; Will, N.; Müller-Duysing, W.; Heinzel, F.; Blum, A. L. Effect of gastric and transpyloric tubes on gastric emptying and duodenogastric reflux. Gastroenterology 1982, 83, 1276−1279. (30) Abuhelwa, A. Y.; Foster, D. J. R.; Upton, R. N. A Quantitative Review and Meta-models of the Variability and Factors Affecting Oral Drug Absorption-Part II: Gastrointestinal Transit Time. AAPS J. 2016, 18, 1322−1333. (31) Weisbrodt, N. W. Patterns of intestinal motility. Annu. Rev. Physiol. 1981, 43, 21−31. (32) Ouyang, A.; Sunshine, A. G.; Reynolds, J. C. Caloric content of a meal affects duration but not contractile pattern of duodenal motility in man. Dig. Dis. Sci. 1989, 34, 528−536. (33) Schiller, C.; Fröhlich, C.-P.; Giessmann, T.; Siegmund, W.; Mönnikes, H.; Hosten, N.; Weitschies, W. Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging. Aliment. Pharmacol. Ther. 2005, 22, 971−979. (34) Mudie, D. M.; Murray, K.; Hoad, C. L.; Pritchard, S. E.; Garnett, M. C.; Amidon, G. L.; Gowland, P. A.; Spiller, R. C.; Amidon, G. E.; Marciani, L. Quantification of gastrointestinal liquid volumes and

ACKNOWLEDGMENTS This work was supported by Grant No. HHSF223201510157C and Grant No. HHSF223201310144C by the U.S. Food and Drug Administration (FDA). This report represents the scientific views of the authors and not necessarily those of the FDA. Bart Hens would like to acknowledge the Internal Funds of KU Leuven (PDM/17/164) and the Council Research of Flanders (FWO: 12R2119N).

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REFERENCES

(1) Food and Drug Administration. Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System: Draft Guidance for Industry; 2015. (2) Food and Drug Administration. Guidance for Industry: Food-Effect Bioavailability and Fed Bioequivalence Studies; 2002. (3) European Medicines Agency. Guideline On The Investigation of Bioequivalence; Doc. Ref: CPMP/EWP/QWP/1401/98; 2010. (4) Pharmaceuticals and Medical Devices Agency. Guideline for Bioequivalence Studies of Generic Products; Division-Notification 0229 No. 10; 2012. (5) Clarysse, S.; Psachoulias, D.; Brouwers, J.; Tack, J.; Annaert, P.; Duchateau, G.; Reppas, C.; Augustijns, P. Postprandial changes in solubilizing capacity of human intestinal fluids for BCS class II drugs. Pharm. Res. 2009, 26, 1456−1466. (6) Müllertz, A.; Reppas, C.; Psachoulias, D.; Vertzoni, M.; Fatouros, D. G. Structural features of colloidal species in the human fasted upper small intestine. J. Pharm. Pharmacol. 2015, 67, 486−492. (7) Camilleri, M.; Malagelada, J. R.; Brown, M. L.; Becker, G.; Zinsmeister, A. R. Relation between antral motility and gastric emptying of solids and liquids in humans. American Journal of Physiology-Gastrointestinal and Liver Physiology 1985, 249, G580. (8) Collins, P. J.; Horowitz, M.; Maddox, A.; Myers, J. C.; Chatterton, B. E. Effects of increasing solid component size of a mixed solid/liquid meal on solid and liquid gastric emptying. Am. J. Physiol. 1996, 271, G549−554. (9) Horowitz, M.; Maddern, G. J.; Chatterton, B. E.; Collins, P. J.; Harding, P. E.; Shearman, D. J. Changes in gastric emptying rates with age. Clin. Sci. 1984, 67, 213−218. (10) Calbet, J. A.; MacLean, D. A. Role of caloric content on gastric emptying in humans. J. Physiol. (Oxford, U. K.) 1997, 498 (2), 553− 559. (11) Kwiatek, M. A.; Menne, D.; Steingoetter, A.; Goetze, O.; ForrasKaufman, Z.; Kaufman, E.; Fruehauf, H.; Boesiger, P.; Fried, M.; Schwizer, W.; Fox, M. R. Effect of meal volume and calorie load on postprandial gastric function and emptying: studies under physiological conditions by combined fiber-optic pressure measurement and MRI. Am. J. Physiol. Gastrointest. Liver Physiol. 2009, 297, G894−901. (12) Vist, G. E.; Maughan, R. J. The effect of osmolality and carbohydrate content on the rate of gastric emptying of liquids in man. J. Physiol. (Oxford, U. K.) 1995, 486 (2), 523−531. (13) Boulby, P.; Moore, R.; Gowland, P.; Spiller, R. C. Fat delays emptying but increases forward and backward antral flow as assessed by flow-sensitive magnetic resonance imaging. Neurogastroenterol. Motil. 1999, 11, 27−36. (14) Houghton, L. A.; Mangnall, Y. F.; Read, N. W. Effect of incorporating fat into a liquid test meal on the relation between intragastric distribution and gastric emptying in human volunteers. Gut 1990, 31, 1226−1229. (15) Nakae, Y.; Onouchi, H.; Kagaya, M.; Kondo, T. Effects of aging and gastric lipolysis on gastric emptying of lipid in liquid meal. J. Gastroenterol. 1999, 34, 445−449. (16) Hens, B.; Brouwers, J.; Anneveld, B.; Corsetti, M.; Symillides, M.; Vertzoni, M.; Reppas, C.; Turner, D. B.; Augustijns, P. Gastrointestinal transfer: in vivo evaluation and implementation in in vitro and in silico predictive tools. Eur. J. Pharm. Sci. 2014, 63, 233−242. J


Article

Molecular Pharmaceutics distribution following a 240 mL dose of water in the fasted state. Mol. Pharmaceutics 2014, 11, 3039−3047. (35) Krieg, B. J.; Taghavi, S. M.; Amidon, G. L.; Amidon, G. E. In vivo predictive dissolution: transport analysis of the CO2, bicarbonate in vivo buffer system. J. Pharm. Sci. 2014, 103, 3473−3490. (36) Potthast, H.; Dressman, J. B.; Junginger, H. E.; Midha, K. K.; Oeser, H.; Shah, V. P.; Vogelpoel, H.; Barends, D. M. Biowaiver monographs for immediate release solid oral dosage forms: ibuprofen. J. Pharm. Sci. 2005, 94, 2121−2131.

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